This invention concerns a process in which fluoroaryl Grignard reagents are converted to fluoroaryl carboxylates via reaction with carbon dioxide.
The carboxylation of Grignard reagents using carbon dioxide is well known in the art, and several carboxylations of fluoroaryl Grignard reagents have been reported. See in this connection U.S. Pat. No. 3,412,162; G.B. Pat. No. 1,027,355; and Vorozhtsov, Jr., et al., Doklady Akademii Nauk SSSR, 1964, 159, 125. These are carried out by bubbling carbon dioxide into a solution of the Grignard reagent; yields tend to be low. A higher yield was achieved by Harper et al., J. Org. Chem., 1964, 29, 2385, using solid carbon dioxide, the use of which is not feasible on a commercial scale.
This invention makes possible the formation of a fluoroaryl carboxylate from a fluoroaryl Grignard reagent via contact with carbon dioxide in significantly higher yields than was previously possible. Furthermore, this process can be carried out in a commercially feasible, highly efficient manner on a continuous basis.
An embodiment of this invention is a process for producing a halomagnesium fluoroaryl carboxylate. This process comprises adding at least one fluoroaryl Grignard reagent to an anhydrous liquid ethereal medium pretreated with carbon dioxide. The aryl group of the fluoroaryl Grignard reagent is a fluorine-containing aryl group, which has bonded directly to an aromatic ring at least two fluorine atoms, or at least two perfluorohydrocarbyl groups, or at least one fluorine atom and at least one perfluorohydrocarbyl group.
Another embodiment of this invention is a continuous process for producing a halomagnesium fluoroaryl carboxylate. This process comprises continuously and concurrently cofeeding carbon dioxide and at least one fluoroaryl Grignard reagent to a reactor, while periodically or continuously removing product solution from the reactor. The aryl group of the fluoroaryl Grignard reagent is a fluorine-containing aryl group, which has bonded directly to an aromatic ring at least two fluorine atoms, or at least two perfluorohydrocarbyl groups, or at least one fluorine atom and at least one perfluorohydrocarbyl group.
Further embodiments of the invention will be apparent from the ensuing description and appended claims.
The fluoroaryl group of the fluoroaryl Grignard reagent has bonded directly to the aromatic ring at least two fluorine atoms, or at least two perfluorohydrocarbyl groups, or at least one fluorine atom and at least one perfluorohydrocarbyl group. It is preferred that at least two fluorine atoms or at least two perfluorohydrocarbyl groups are bonded directly to the aromatic ring. Each position on the aromatic ring(s) of the fluoroaryl group that is not a fluorine atom or a perfluorohydrocarbyl group is substituted by a hydrogen atom, a hydrocarbyl group, an alkoxy group, or a silyl group.
The halogen atom of the halomagnesium moiety of the fluoroaryl Grignard reagent may be a chlorine atom, bromine atom, or iodine atom. Preferred halogen atoms are chlorine and bromine. Thus, the halomagnesium moiety is preferably a bromomagnesium moiety or a chloromagnesium moiety.
Throughout this document, the term xe2x80x9cfluoroaryl groupxe2x80x9d shall be understood, when not specified, to mean, as described above, a fluorine-containing aryl group, which has bonded directly to an aromatic ring at least two fluorine atoms, or at least two perfluorohydrocarbyl groups, or at least one fluorine atom and at least one perfluorohydrocarbyl group. It is preferred that at least two fluorine atoms or at least two perfluorohydrocarbyl groups are bonded directly to an aromatic ring. Each position on the aromatic ring(s) of the fluoroaryl group that is not a fluorine atom or a perfluorohydrocarbyl group is substituted by a hydrogen atom, a hydrocarbyl group, an alkoxy group, or a silyl group. The aromatic ring of the fluoroaryl group may be, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthryl, biphenylyl, phenanthryl, or indenyl. Phenyl is the preferred aromatic moiety. The perfluorohydrocarbyl substituent groups, when present, include alkyl and aryl perfluorocarbons; suitable perfluorohydrocarbyl groups are, for example, trifluoromethyl, pentafluoroethyl, pentafluorophenyl, and heptafluoronaphthyl. The hydrocarbyl groups of the aryl groups are preferably C1 to C18 alkyl groups or C6 to C20 aryl or aralkyl groups. Examples of suitable hydrocarbyl groups are methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, methylcyclohexyl, decyl, phenyl, tolyl, xylyl, benzyl, naphthyl, and tetrahydronaphthyl. The alkoxy groups preferably have C1 to C6 alkyl moieties. Some examples of alkoxy groups are methoxy, ethoxy, isopropoxy, methylcyclopentoxy, and cyclohexoxy. The silyl groups preferably have C1 to C18 alkyl groups or C6 to C20 aryl or aralkyl groups. Suitable silyl groups include trimethylsilyl, triisopropylsilyl, tert-butyl(dimethyl)silyl, tridecylsilyl, and triphenylsilyl. Examples of fluoroaryl groups that can be part of the Grignard reagent in this invention include 3,5-bis(trifluoromethyl)phenyl, 2,4,6-tris(trifluoromethyl)-phenyl, 4-[tri(isopropyl)silyl]-tetrafluorophenyl, 4-[dimethyl(tert-butyl)silyl]-tetrafluorophenyl, 4xe2x80x2-(methoxy)-octafluorobiphenylyl, 2,3-bis(pentafluoroethyl)-naphthyl, 2-(isopropoxy)-hexafluoronaphthyl, 9,10-bis(heptafluoropropyl)-heptafluoroanthryl, 9,10-bis(p-tolyl)-heptafluorophenanthryl, and 1-(trifluoromethyl)-tetrafluoroindenyl. It is preferred that at most two substituents on the ring of the fluoroaryl group are hydrocarbyl, perfluorohydrocarbyl, or alkoxy.
It is highly preferred to have fluoroaryl groups in which all of the substituents are fluorine atoms. Examples of such groups are pentafluorophenyl, 4-nonafluorobiphenylyl, 2-nonafluorobiphenylyl, 1-heptafluoronaphthyl, 2-heptafluoronaphthyl, 7-nonafluoroanthryl, 9-nonafluorophenanthryl, and analogous groups. The most highly preferred perfluoroaryl group is pentafluorophenyl.
Preferred fluoroaryl Grignard reagents include pentafluorophenylmagnesium bromide, heptafluoronaphthylmagnesium chloride, 2-nonafluorobiphenylylmagnesium chloride, 3,5-bis(trifluoromethyl)phenyl bromide, and 2,3-bis(pentafluoroethyl)-naphthylmagnesium chloride. The most highly preferred fluoroaryl Grignard reagents are pentafluorophenylmagnesium bromide and pentafluorophenylmagnesium chloride.
A feature of this invention is pretreatment of a liquid ethereal medium with carbon dioxide prior to the introduction of the fluoroaryl Grignard reagent to the liquid ethereal medium. The liquid ethereal medium that is pretreated with carbon dioxide is comprised of one or more liquid ethers. Any of a variety of monoethers or polyethers may be used, and they may be aliphatic, aromatic, alkylaromatic, and/or cyclic ethers. Examples of ethers that may be used include diethyl ether, ethyl n-propyl ether, di-n-propyl ether, diisopropyl ether, di-n-butyl ether, n-butyl methyl ether, cyclohexyl methyl ether, methoxybenzene, n-butyl phenyl ether, dibenzyl ether, o-xylylene oxide (phthalan), 1,4-benzodioxan, dihydrobenzopyran (chroman), isochroman, trimethylene oxide, 3,3-dimethyltrimethylene oxide, tetrahydrofuran, methyl tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolane, 1,3-dioxepane, glyme (the dimethyl ether of ethylene glycol), diglyme (the dimethyl ether of diethylene glycol), triglyme, and tetraglyme. Unsubstituted cyclic ethers are preferred. Thus, preferred ethers include tetrahydrofuran, tetrahydropyran, 1,3-dioxane, and 1,3-dioxolane. Tetrahydrofuran is an especially preferred liquid ethereal medium in the practice of this invention.
The fluoroaryl Grignard reagent is in a liquid medium. Normally and preferably, this liquid medium is one or more ethers. Ethers in which the fluoroaryl Grignard reagent can be include, for example, those described above for the liquid medium that is pretreated with carbon dioxide. An especially preferred ether for the fluoroaryl Grignard reagent in this invention is tetrahydrofuran. Although not required, the liquid medium in which the fluoroaryl Grignard reagent is dissolved is preferably the same ether or mixture of ethers that is used as the liquid ethereal medium which is pretreated with carbon dioxide.
As is well known in the art, Grignard reagents require anhydrous conditions. Anhydrous conditions are thus necessary for the carboxylation of the fluoroaryl Grignard reagent. The reaction is preferably conducted in an inert atmosphere or, more preferably, in an atmosphere of dry (i.e., anhydrous) carbon dioxide. Another preferred embodiment is the use of mixtures of inert gas(es) and dry carbon dioxide. Inert gases are well known in the art and include, for example, nitrogen, helium, and argon.
Prior to contact with the fluoroaryl Grignard reagent, liquid ethereal medium is pretreated with carbon dioxide. To increase the amount of carbon dioxide in the liquid ethereal medium, the partial pressure of carbon dioxide can be increased. Superior results are achieved at increased pressures; thus, carbon dioxide pressures greater than atmospheric pressure are preferred. Such partial pressures of carbon dioxide are preferably in the range of from about 5 psig to about 100 psig. More preferred are carbon dioxide pressures in the range of from about 20 psig to about 40 psig. It is further preferred that the increased carbon dioxide pressure is maintained throughout the carboxylation reaction.
In one embodiment, the fluoroaryl Grignard reagent is added to the liquid ethereal medium that is pretreated with carbon dioxide. Addition of the fluoroaryl Grignard reagent can be slow (e.g., dropwise), fast, or at intermediate speeds. The rate of addition of the fluoroaryl Grignard reagent does not appear to affect the yield of the reaction. Additional carbon dioxide can be, and preferably is, added concurrently with the addition of the fluoroaryl Grignard reagent. It is also preferred to add additional carbon dioxide during any further mixing time after the addition of the fluoroaryl Grignard reagent is finished.
On the laboratory scale, a preferred contact time for the components of the reaction is in the range of from about five minutes to about six hours. More preferably, the contact time is from about ten minutes to about three hours. Without being bound by theory, it is believed that the reaction of the fluoroaryl Grignard reagent and carbon dioxide is mass transport limited. Thus, if desired, conditions can be optimized so that contact times are quite short (e.g., minutes).
The carboxylation reaction can be conducted in a wide temperature range, so long as the temperature is below the thermal decomposition temperature of the reactants and desired products of the reactions, and the reaction mixtures are in the liquid state under the temperature and pressure conditions being used. Reaction temperatures are often within the range of from about 0xc2x0 C. to about 60xc2x0 C. However, temperatures in the range from about xe2x88x9230xc2x0 C. to about 25xc2x0 C. usually result in higher yields of the carboxylated product, and temperatures in this range are preferred. More preferred are temperatures in the range of from about xe2x88x9220xc2x0 C. to about 1xc2x0 C. Temperatures in the range of from about xe2x88x9220xc2x0 C. to about 0xc2x0 C. are highly preferred. Depending on the temperature(s) at which the reaction is conducted, particularly for lower temperatures, care must be taken in the selection of the ether or ethers which comprise the liquid ethereal medium so that the medium is not a solid at the desired reaction temperature.
The halomagnesium fluoroaryl carboxylates produced by this invention can be hydrolyzed to form the corresponding carboxylic acid, or reacted with a metal salt (such as, for example, sodium chloride) to form the desired carboxylate salt.
A further advantage of this invention is that continuous operation is now possible. When initiating continuous operations, liquid ethereal medium pretreated with carbon dioxide is present in the reactor. Fluoroaryl Grignard reagent and carbon dioxide are continuously and concurrently co-fed to the reactor; however, the initiation of such feeds need not be concurrent. When the feed of fluoroaryl Grignard reagent to the reactor is started, or more preferably at some time thereafter, removal of product solution can be initiated. Periodic or continuous removing of product solution, once begun, is preferably maintained continuously and concurrently while fluoroaryl Grignard reagent is being fed. So long as the pressure of carbon dioxide in the reactor is maintained, further addition of liquid ethereal medium pretreated with carbon dioxide is not necessary. Liquid ethereal medium lost by removing product solution is replaced by liquid medium of the fluoroaryl Grignard reagent feed. It is possible to separately feed liquid ethereal medium to the reactor, although such an operation offers no particular advantage. Further, more than one feed of fluoroaryl Grignard reagent and/or carbon dioxide may be used, but again no advantage is gained by doing so. Once the solution has been drained from the reactor, the halomagnesium fluoroaryl carboxylate product can be stored, hydrolyzed, or reacted with a metal salt.
If the reaction is performed in a reactor of sufficient size, the volume of the reactor contents can be cycled between predetermined low and high volumes with initiation of rapid removal when the volume reaches the high volume of reactor contents, and with discontinued removal once the volume reaches the low volume of reactor contents. However, it is preferred to conduct the process so that the volume of the contents of the reactor and portion of the solution removed from the reactor are equal or substantially equal whereby the volume of reactor contents remains constant or substantially constant. In this way, reactors with smaller volumes can be employed.
Thus, once steady-state conditions have been achieved in a continuous reactor, the separate feeds can be fed on a continuous basis, and the reactor contents maintained under the appropriate reaction conditions for virtually unlimited periods of time. Concurrently, a portion of the solution is being removed, usually and preferably continuously, from the reaction mixture so that the volume of the contents of the reactor remains more or less constant.
When operating in a continuous mode and once the continuous feeds have been initiated, the feeds may be adjusted in fine tuning the operation so as to establish and maintain the desired operating conditions for the steady-state operation. Such operation typically can be conducted without mishap for long periods of time before shutdown, e.g., for plant maintenance.
While less preferred, semi-continuous operation is also within the scope of this invention. In semi-continuous operations, fluoroaryl Grignard reagent is fed to at least one and then to at least one other of at least two reactors, which contain anhydrous liquid ethereal medium pretreated with carbon dioxide. While fluoroaryl Grignard reagent is being fed to a reactor, product solution can be, and preferably is, removed from that reactor. Removal of product solution can be initiated when the feed of fluoroaryl Grignard reagent to the reactor containing the medium that is pretreated with carbon dioxide is started, or more preferably at some time thereafter. Most preferably, the solution of fluoroaryl Grignard reagent is being fed continuously or substantially continuously into a reactor containing the medium that is pretreated with carbon dioxide while concurrently and continuously removing a portion of the solution from the reactor. On the laboratory scale, the residence time is typically in the range of from about 25 minutes to about 45 minutes.
In semi-continuous processes, during the time the fluoroaryl Grignard reagent is being fed to at least one of at least two reactors in which there is liquid ethereal medium pretreated with carbon dioxide, additional liquid ethereal medium pretreated with carbon dioxide can be prepared in at least one other of such reactors to which fluoroaryl Grignard reagent is not then being added. In this way, fluoroaryl Grignard reagent can be continuously added to one or more reactors as a continuous feed, while more liquid ethereal medium is pretreated with carbon dioxide in one or more other reactors. Thus, when one reactor is depleted of carbon dioxide, the feed of fluoroaryl Grignard reagent is switched to another reactor which then serves as the receiving reactor for the continuous feed of fluoroaryl Grignard reagent until that reactor is depleted of carbon dioxide, and by that time more of such liquid ethereal medium has been pretreated with carbon dioxide in another reactor. Thus by alternating the production from one reactor (or group of reactors) to another reactor (or group of reactors) and switching back and forth between the reactors, the continuous feed of the fluoroaryl Grignard reagent to liquid ethereal medium pretreated with carbon dioxide can be maintained without material interruption. One way to determine that a reactor has been depleted of liquid ethereal medium pretreated with carbon dioxide is to monitor the carbon dioxide pressure; if it no longer decreases, the carbon dioxide has been depleted.
A particularly preferred embodiment of the above continuous and semi-continuous processes includes the following concurrent operation, namely, continuously withdrawing fluoroaryl Grignard reagent from a reaction vessel, and during the time the fluoroaryl Grignard reagent is being withdrawn from the vessel, forming additional fluoroaryl Grignard reagent in the same reaction vessel. In this way, fluoroaryl Grignard reagent can be continuously withdrawn from a reaction vessel to serve as a continuous feed, while forming more of such fluoroaryl Grignard reagent. Thus, the continuous feed of the fluoroaryl Grignard reagent can be maintained without material interruption.
Another, less preferred embodiment of the above continuous and semi-continuous processes includes the following concurrent operation, namely, continuously, but alternately, withdrawing from at least one and then from at least one other of at least two reaction vessels, fluoroaryl Grignard reagent. During the time the fluoroaryl Grignard reagent is being withdrawn from at least one of at least two such reaction vessels, additional fluoroaryl Grignard reagent is formed in at least one other of such reaction vessels from which solution is not then being withdrawn. In this way, fluoroaryl Grignard reagent can be continuously withdrawn from one or more vessels to serve as a continuous feed, while forming more of such fluoroaryl Grignard reagent in one or more other vessels, so that when one vessel is depleted, the system is switched to another vessel which then serves as the supply for the continuous feed until depleted, and by that time more of such fluoroaryl Grignard reagent has been formed in another vessel. Thus by alternating the supply and the production from one vessel (or group of vessels) to another vessel (or group of vessels) and switching back and forth between the filled vessels as the supply, the continuous feed of the fluoroaryl Grignard reagent can be maintained without material interruption.
Some processes of this invention are continuous or semi-continuous processes and involve continuous feeds. In addition, some embodiments of the invention involve continuous formation of fluoroaryl Grignard reagent. In such embodiments, the term xe2x80x9ccontinuousxe2x80x9d or xe2x80x9ccontinuouslyxe2x80x9d is not meant to exclude interrupted feeds. Generally, if such interruptions occur, they are of short duration and are such as not to materially affect the operation of the overall process. An example of such a slight, non-adverse interruption may occur when switching the flow of fluoroaryl Grignard reagent from at least one reactor to another such reactor, an operation which is referred to above as part of a xe2x80x9ccontinuousxe2x80x9d feed. As long as such switching operation does not disrupt the operation, such interruption is acceptable and is within the spirit of the term xe2x80x9ccontinuousxe2x80x9d. Those skilled in the art will of course seek to maintain the continuous feeds with as few interruptions as possible under the given circumstances in which the operation is being conducted.
The term xe2x80x9cconcurrentxe2x80x9d is used in the sense that during substantially the entire reaction period, the designated feeds are being maintained. The use of the term xe2x80x9cconcurrentxe2x80x9d does not exclude the possibility of inconsequential interruptions taking place during the feeds. Nor does this term imply that the feeds must start at exactly the same moment in time. In the case of a co-feed process, the two feeds can be initiated with an interval of time between such initiation as long as the interval is sufficiently short as to cause no material adverse effect upon the overall process. Likewise in the case of a multi-feed operation, there may be one or two different time intervals between or among the respective feeds, again provided that the time intervals are of sufficiently short duration to cause no material adverse effect upon the overall process. Naturally, those skilled in the art will strive to utilize the concurrent feeds with as little nonconcurrence as possible.
It should be understood that while the concurrent feeds are preferably continuous concurrent feeds, slight interruptions in a feed are acceptable provided that the duration of the interruption is sufficiently small as to cause no material disruption in the reaction. Thus as used herein, the terms xe2x80x9cconcurrentxe2x80x9d and xe2x80x9ccontinuousxe2x80x9d should be understood to embrace the minor departures just referred to.
The fluoroaryl Grignard reagent can be made by reacting either magnesium metal or a hydrocarbyl Grignard reagent with a fluoroaromatic compound which has a chlorine atom, a bromine atom, or an iodine atom directly bonded to an aromatic ring of the compound. Other substituents for the fluoroaromatic compound are as described above for the fluoroaryl groups of the fluoroaryl Grignard reagent. That is, directly bonded to an aromatic ring are at least two fluorine atoms, or at least two perfluorohydrocarbyl groups, or at least one fluorine atom and at least one perfluorohydrocarbyl group. Each position on the aromatic ring(s) of the fluoroaryl group that is not a chlorine atom, a bromine atom, or an iodine atom, or a fluorine atom or a perfluorohydrocarbyl group, is a hydrogen atom, a hydrocarbyl group, an alkoxy group, or a silyl group. Examples of suitable fluoroaromatic compounds include, but are not limited to, chloropentafluorobenzene, bromopentafluorobenzene, 1-chloro-2,4,6-tris(trifluoromethyl)-benzene, 1-bromo-2-(isopropoxy)-hexafluoronaphthalene, and 1-chloro-9,10-bis(heptafluoropropyl)-heptafluoroanthracene. The most highly preferred fluoroaromatic compound is chloropentafluorobenzene. It is preferred to use magnesium metal in the reaction with the fluoroaromatic compound.
Forms of magnesium metal that can be used in the reaction to make the fluoroaryl Grignard reagent include turnings, powder, chips, granules, and the like. The preferred form of magnesium metal in this invention is granules. When magnesium metal is used, it is preferably in molar excess of the amount of fluoroaromatic compound used. The preferred molar ratio is in the range of from about 1.01 mole of magnesium metal per mole of fluoroaromatic compound to about 2.0 moles of magnesium metal per mole of fluoroaromatic compound. Most desirable is a molar ratio of about 1.15 to about 1.5 mole magnesium metal per mole fluoroaromatic compound.
For the hydrocarbyl Grignard reagent used to make the fluoroaryl Grignard reagent, the word hydrocarbyl is defined as any monovalent group derived from a linear, branched, or cyclic C1 to C20 hydrocarbon. Examples of hydrocarbyl Grignard reagents include ethylmagnesium chloride, sec-butylmagnesium bromide, cyclopentenylmagnesium chloride, cyclohexylmagnesium bromide, 3-hexenylmagnesium iodide, 4-methylcyclooctylmagnesium iodide, 6-ethyldodecylmagnesium bromide, and eicosylmagnesium chloride. Short-chain alkyl Grignard reagents, e.g., C1 to C6, are preferred hydrocarbyl Grignard reagents, and the preferred halogen atom of the hydrocarbyl Grignard reagent is a bromine atom. Ethylmagnesium bromide is the most highly preferred hydrocarbyl Grignard reagent.
When a hydrocarbyl Grignard reagent is used to make the fluoroaryl Grignard reagent, it is preferably in molar excess of the amount of fluoroaromatic compound used. The preferred molar excess of hydrocarbyl Grignard reagent is in the range of from about 1.01 mole of hydrocarbyl Grignard reagent per mole of fluoroaromatic compound to about 1.2 mole of hydrocarbyl Grignard reagent per mole fluoroaromatic compound. Most desirable is a molar excess of about 1.05 to about 1.15 mole of hydrocarbyl Grignard reagent per mole of fluoroaromatic compound.